Protein homeostasis mechanisms underlying enterovirus replication and evolution

描述(由申请人提供)： 这项建议的重点是剖析蛋白质稳态在肠道病毒复制、进化和发病机制中的作用。这些研究的范例是，肠道病毒高度依赖细胞伴侣和质量控制(QC)机制来产生蛋白质和发挥功能。此外，鉴于这些病毒的高突变率，我们假设伴侣和QC网络是调节病毒多样性、进化和致病的关键。我们建议研究宿主蛋白质稳态机制如何参与肠道病毒复制和调节病毒多样性，以及病毒如何利用这一机制来减轻复制过程中积累的突变的有害影响。我们最近已经证明，肠道病毒的高突变率对它们的适应性和致病作用是必不可少的。因此，通过调节蛋白质稳态机制来限制病毒的多样性可以提供有效的途径来减弱病毒的致病作用。这一建议结合了计算、细胞生物学、分子和系统的方法来定义与肠道病毒复制有关的宿主蛋白稳态网络，并确定该网络在病毒进化、多样性和致病机制中的作用。鉴于传统策略未能实现对肠道病毒(如脊髓灰质炎、柯萨奇病毒和肠道病毒71型)的任何治疗性干预，这些新的方法是必不可少的，它有可能为预防当前和新出现的肠道病毒疾病奠定基础。这份提案描述了一种多学科和高度整合的方法，旨在获得这一至关重要的信息。我们提出了3个具体项目和2个核心：项目1：通过对细胞网络的全球分析揭示宿主-肠道病毒回路；项目2：细胞因子在肠道病毒蛋白质稳态和功能中的作用；以及项目3：蛋白质稳态在肠道病毒种群多样性、进化和致病中的作用。核心A：行政核心；核心B：“高通量功能基因组学和蛋白质组学核心。

DESCRIPTION (provided by applicant): The focus of this proposal is to dissect the role of Protein Homeostasis in enterovirus replication, evolution and pathogenesis. The paradigm for these studies is that enteroviruses are highly dependent on the cellular chaperone and quality control (QC) machinery for their protein production and function. Furthermore, given the very high mutation rates of these viruses, we hypothesize that the chaperones and QC network is key to modulating virus diversity, evolution and pathogenesis. We propose to examine how host protein homeostasis machinery participates in enterovirus replication and modulates viral diversity and how viruses use this machinery to alleviate the detrimental effect of mutations that accumulate during replication. We have recently demonstrated that high mutation rate of enteroviruses is essential for their adaptability and pathogenesis. Thus, restricting viral diversity through the modulation of protein homeostasis machinery could provide powerful ways to attenuate virus pathogenesis. This proposal combines computational, cell biological, molecular and systems approaches to define the host protein homeostasis network involved in enteroviral replication and determine the role of this network to viral evolution, diversity, and pathogenesis. These new approaches are essential given the failure of traditional strategies to achieve any therapeutic intervention against enteroviruses (such as polio, coxsackie, and enterovirus 71) and it has the potential to set the basis for the prevention of current and emerging enteroviral diseases . This proposal describes a multidisciplinary and highly integrated approach that is designed to obtain this critically important information. We propose 3 Specific Projects and 2 Cores: Project 1: Host-enterovirus circuitry revealed by global analysis of cellular networks; Project 2: Role of cellular factors in enterovirus protein homeostasis and function; and Project 3: Role of protein homeostasis in enterovirus population diversity, evolution and pathogenesis. Core A: Administrative Core; and Core B: "High-throughput functional genomics and proteomics core.